PNNL

Abstract

The PARM99 version of the AMBER force field1 was used in the NWChem computational chemistry package2 to carry out molecular dynamics (MD) simulations on the fully solvated and cation neutralized DNA oligonucleotide GGGAACAACTAG:CTAGTTGTTCCC in its native form and with guanine in the central G19:C6 base pair replaced by 8-oxoguanine (8oxoG). The direction and magnitude of global bending were assessed by a technique used preciously to analyze simulations of DNA containing a thymine dimer3. The presence of 8oxoG did not greatly affect the magnitude of DNA bending; however, bending directions that compress the major groove and expand the minor groove were significantly more probable when 8oxoG replaced G19. Crystal structures of glycosylases bound to damaged-DNA substrates4-7 consistently show bending that expands the minor groove. We conclude that changes in bending dynamics that facilitates this expansion are part of the mechanism by which 8oxoG is recognized by the base excision repair pathway.